The overall objective of the proposed research is the total synthesis of the natural product K-76. More importantly, minor modifications of the synthesis would allow preparation of analogues not available from biological sources which would exhibit greater potency and lower toxicity (a higher therapeutic ratio) than the natural product which is quite toxic. Our strategies for total synthesis of K-76 involve union of an AB-ring synthon with a D-ring synthon and subsequent heterocyclization to give the C-ring in analogy with the presumed biosynthesis. K-76 blocks the complement cascade (both classical and alternative) after generation of the membrane bound "activation unit". Activation of C5 does not occur and the biologically active "chemotactic factor" peptide C5a is not generated. Other compounds with such highly selective ability to block the complement cascade at C5 are unknown. Most significantly, drugs with this biological activity are very likely to be of great medicinal utility for several reasons. Thus, many of the beneficial effects of the complement cascade in the defense against infection do not depend on the "membrane attack unit" since adequate protection is afforded by opsonizing antibodies and the immune adherence mechanisms. On the other hand, the complement cascade is involved in certain hypersensitivity reactions and can be activated chaotically in such situations as extracorporeal perfusion, trauma, sepsis, or acute pancreatitis. The activation peptide C5a can have many undesirable biological effects owing to its ability to cause granulocyte aggregation. The resulting leukoembolization ultimately may cause tissue damage. Administration of drugs based on K-76 might diminish tissue damage of acute myocardial infarction, prevent retinopathy after severe trauma, prevent extension of infarctive damage of ulcerated atherosclerotic plaques, or block complement-dependent hypersensitivity, e.g. certain drug reactions. Preliminary results have already demonstrated that the sodium salt of K-76 monocarboxylic acid 22 improves the symptoms of experimental glomerulonephritis in rats.